Polyphosphonic acids and their pharmaceutical acceptable salts have been known for use in the treatment of diseases of bone and calcium metabolism. Several methods for making bisphosphonates have been described in the literature, for example Pamidronic acid, Alendronic acid, Risedronic acid and Zoledronic acid. These compounds have very less solubility in water, and hence can be easily isolated from the water. Whereas Ibandronic acid is easily soluble in water, as a result its isolation from water is very difficult.
U.S. Pat. No. 4,927,814 describes the process to make analogues of Ibandronic acid which involves the use of chlorobenzene, phosphorous acid and phosphorous trichloride and finally the Ibandronic acid is isolated by using Ion exchange resin chromatography, employing Amberlite IR-120 H+ column and eluted with water where elution is monitored electrophoretically. However these operations are very difficult and time consuming on an industrial scale. This patent claims broadly Ibandronate sodium but there is no exemplary disclosure for making Ibandronate sodium.
WO2005/044831 describes the process to make analogues of Ibandronic acid by using sulfolane as a solvent instead of chlorobenzene and isolating the acids from water. While the technique described for the isolation can be used for Pamidronic acid, Alendronic acid, Risedronic acid, and Zoledronic acid, this process cannot be used for isolating Ibandronic acid because of its high solubility in water.
WO2005/063779 describes the process to make Risedronic acid by adding acetone to the aqueous solution of Risedronic acid, and then isolating the acid. However this process also works well for Pamidronic acid, Alendronic acid, Risedronic acid, and Zoledronic acid even without addition of acetone, but the same process does not work for Ibandronic acid because of its high solubility in water.
Ibandronic acid being highly soluble in water does not precipitate out even after addition of solvent.
In the prior art processes, bisphosphonic acids like zoledronic acid, pamidronic acid, alendronic acid, risedronic acid etc. have been prepared by the reaction of corresponding carbonyl compounds (FIG. 1) with phosphorous acid, phosphorous halides, (example: phosphorous trichloride, phosphorous oxychloride, or phosphorous pentachloride) and then quenching the reaction mixture with water, heating the reaction mass to get bisphosphonic acid which is isolated and converted to the sodium salt of respective acid.

Similar procedure (FIG. 2) is reported to be adopted for preparing ibandronate sodium. But isolation of ibandronic acid from water and converting it to sodium salt is cumbersome and difficult process because of the high solubility of ibandronic acid in water.

The prior art further discloses various methods for the synthesis of compound (III), which is the key intermediate in the synthesis of Ibandronate sodium. U.S. Pat. No. 4,927,814, Drugs of Future 1994, 19(1), 13-16 describes a process wherein N-methyl pentyl amine is reacted with methyl acrylate to give the corresponding methyl ester which is further hydrolyzed to get compound (III).
Initially various attempts were made to synthesize the intermediate III. Scheme II shows two new alternate schemes for the synthesis of III which employs the use of methyl acrylate.
The processes described in the prior art involves the use of methyl acrylate, which is very obnoxious reagent, polymerizes on storage and needs to be distilled before using. This reagent is toxic, unstable; hence it is not preferred to be used on an industrial scale.
Further efforts were made for the synthesis of III which avoids the use of methyl acrylate, this was achieved by using methyl 3-bromopropionate as shown in Scheme I.
Therefore there is need for a simple, economical and industrially viable process for the synthesis of Ibandronate sodium.
The present invention provides a simple process for the synthesis of ibandronate sodium and its intermediate 3-[N-(methylpentyl)amino]propionic acid (III).